Methods and compositions to inhibit dependence on opioids

ABSTRACT

The present invention provides a method of inhibiting dependence to an opioid by a human subject in need thereof. The method comprises administering an effective amount of a pharmaceutical composition to the subject during opioid therapy. The pharmaceutical composition comprises a) a non-steroidal anti-inflammatory drug (NSAID); and b) a co-agent selected from the group consisting of: fexofenadine, ketotifen, desloratadine, cetirizine, salts thereof and combinations thereof.

FIELD OF THE INVENTION

The present invention relates to methods, and compositions, forinhibiting the dependence on opioids during opioid therapy.

BACKGROUND OF THE INVENTION

Opioids are a class of drugs that include the illegal drug heroin andanalgesics available legally by prescription, such as oxycodone(OxyContin®), hydrocodone (Vicodin®), codeine and morphine. Opioids arepowerful pain relievers, but their use is hindered by tolerance to theanalgesic effects, physical dependence resulting in withdrawal syndrome,and the possibility of addiction.

Dependence is characterized by physical or psychological withdrawalsymptoms upon discontinuation of an opioid. Dependence may beindependent of addiction. However, physical dependence, or the desire toavoid withdrawal symptoms, is thought to contribute to opioid addiction,particularly at later stages of addiction; whereas, a craving for theeuphoric effects of opiates may dominate in earlier stages (Burns, L,Recent Developments in Pain Research, 11-136 (2005)). The somaticwithdrawal signs that can occur when opioid therapy is abruptly stoppedin physically dependent individuals include agitation, irritability,muscular ailments, abdominal pain, diarrhea, burning sensations,“gooseflesh,” and itching. In an effort to minimize withdrawal symptoms,patients are required to be carefully tapered off of the opioid.However, such approach requires strict monitoring throughout an extendedprotocol.

Due to the potential dire consequences of opioid use, there is an urgentneed to enable an efficient cessation of opioid use with minimalwithdrawal symptoms.

SUMMARY OF THE INVENTION

In one embodiment, the present invention is a method of inhibitingdependence to an opioid by a human subject in need thereof. The methodcomprises administering an effective amount of a pharmaceuticalcomposition to the subject during opioid therapy. The pharmaceuticalcomposition comprises a) a non-steroidal anti-inflammatory drug (NSAID);and b) a co-agent selected from the group consisting of: fexofenadine,ketotifen, desloratadine, cetirizine, salts thereof and combinationsthereof.

In one embodiment, the NSAID is aspirin, ibuprofen, naproxen,diclofenac, diflunisal, etodolac, indomethacin, ketoprofen, ketorolac,meloxicam, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, and/ortolmetin.

In one embodiment, the NSAID is ibuprofen and the co-agent isfexofenadine. In one embodiment, the amount of ibuprofen is about 150 mgto about 900 mg, and the amount of fexofenadine is about 60 mg to about180 mg. In one embodiment, the ibuprofen and the fexofenadine iscombined in one unit dose. In one embodiment, the ibuprofen and thefexofenadine is in the form of a tablet, lozenge or chewing gum.

In one example, the NSAID is ibuprofen and the co-agent is ketotifen. Inone embodiment, the amount of ibuprofen is about 1200 mg to about 1600mg, and the amount of ketotifen is about 0.5 mg to about 4 mg, e.g., adaily dose of about 2400 mg to about 3200 mg of ibuprofen and about 2 mgof ketotifen. In one embodiment, the ibuprofen and the ketotifen iscombined in one unit dose. In one embodiment, the ibuprofen and theketotifen is in the form of a tablet, lozenge or chewing gum.

In one embodiment, the present invention is a pharmaceutical compositioncomprising a) an NSAID, and/or a salt thereof; and b) a co-agentselected from fexofenadine, ketotifen, desloratadine, cetirizine saltsthereof and combinations thereof. In one embodiment, the pharmaceuticalcomposition is ibuprofen in an amount of about 150 mg to about 900 mg,and fexofenadine in an amount of about 25 mg to about 200 mg. In oneembodiment, the NSAID is ibuprofen and the co-agent is ketotifen. In oneembodiment, the amount of ibuprofen is about 800 mg to about 1600 mg,and the amount of ketotifen is about 2 mg.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the present invention is directed to methods ofinhibiting the dependence on opioids in human subjects. The methodsinclude the administration of particular pharmaceutical compositions.

Throughout this specification, quantities are defined by ranges, and bylower and upper boundaries of ranges. Each lower boundary can becombined with each upper boundary to define a range. The lower and upperboundaries should each be taken as a separate element.

Opioids are substances that act by binding to opioid receptors, whichreceptors are found principally in the central and peripheral nervoussystem and the gastrointestinal tract. These receptors mediate both thepsychoactive and the somatic effects of opioids. Medically opioids areprimarily used for pain relief, including anesthesia. Other medical usesinclude suppression of diarrhea and suppressing cough.

Opioids include opiates, which are alkaloid compounds naturally found inthe opium poppy plant (i.e., Papaver somniferum). The psychoactivecompounds found in the opium plant include opium, heroin, morphine,codeine and thebaine. Examples of synthetic, or semi-synthetic, opioidsinclude hydrocodone (e.g., Vicodin®, Lorcet®, Lortab®, Percocet®,Percodan®); oxycodone (e.g., OxyContin®); fentanyl (e.g., Duragesic®);methadone (Dolophine®); pethidine (e.g., Demerol®) and hydromorphone(e.g., Dilaudid®)

Opioid therapy is the treatment of a human subject with opioids,typically a prolonged treatment with opioids, typically to achieveanalgesic effects.

The methods of the present invention comprise the administration of apharmaceutical composition to a human subject, in need thereof, in anamount which is effective to inhibit the physical dependence on opioidsby the subject. A human subject in need thereof is a human who is toreceive, or is receiving, opioid therapy. Administration includesadministration by a physician or by self-administration.

Physical dependence on an opioid is a state of adaptation by a patientwho has received the opioid for a period of time and who experiences, orwould experience, withdrawal syndrome if the opioid is abruptlywithdrawn or if a narcotic antagonist (e.g., naloxone) is administered.Physical dependence is a normal physiological response.

Opioid withdrawal syndrome includes symptoms which may range from mildto severe, depending on how dependent the subject is on the opioid.Dependency can be directly tied to the length of time taking an opioid,dosage amount, which particular opioid was taken, route ofadministration, underlying medical conditions, mental health, andcertain biological and environmental factors, such as family history ofaddiction, previous trauma, and stressful surroundings.

Withdrawal from an opioid may roughly adhere to the following timeline,although it can vary from subject to subject. Early withdrawal symptomstypically start within 6-12 hours after last dose is taken forshort-acting opioids, and start within 30 hours after last dose is takenfor longer-acting opioids. Early withdrawal symptoms include:lacrimation, muscle aches, agitation, insomnia, excessive yawning,anxiety, panic, rhinorrhea, sweating, tachycardia, hypertension andfever. Late withdrawal symptoms typically peak within 72 hours afterlast dose is taken, usually lasting about a week, and include nausea andvomiting, diarrhea, piloerection, stomach cramps, depression, and drugcravings. Other withdrawal symptoms may include, for example, mydriasis,restlessness; tremor; involuntary movements; muscle twitches; abdominalcramps; cold flashes; substantial physical and mental fatigue; dysphoricmood; drowsiness; salivation; loss of appetite; headache; dizziness;fainting; malaise; shivering; muscle/joint pain; irritability; poorconcentration; confusion; flu-like symptoms; and the like.

When administered the pharmaceutical composition, the dependence on anopioid is inhibited. One manner by which dependence is inhibited is byreducing the amount of opioid required to achieve a certain therapeuticeffect (e.g., analgesic effect) for a subject. That is, the amount of anopioid given is directly related to any dependence that may develop.However, dependence to an opioid is inhibited by the methods of thepresent invention even if the opioid amount is not reduced.

The pharmaceutical composition is administered to the human subject, inneed thereof, during opioid therapy, optionally, slightly before thecommencement of opioid therapy. For example, administration is begun atmost about 48 hours before the first dose of an opioid or at the time ofthe first dose of an opioid, and is substantially continued for theduration of the opioid therapy. Alternatively, administration can bebegun at any point during opioid therapy.

In the present specification, the term “inhibit” includes “reduce”and/or “prevent” and/or “shorten duration.” That is, the methods of thepresent invention are considered to be effective if they cause one ormore of: a reduction/prevention of dependence on an opioid and/orshortening of the duration of any dependence to an opioid. For example,dependence would be inhibited if upon cessation of opioid therapy,withdrawal symptoms are inhibited.

Inhibition of dependence can be assessed by comparing the magnitudeand/or duration of dependence in a subject at two different occasions,that is, i) when administered the pharmaceutical composition during anopioid therapy; and ii) when not administered the pharmaceuticalcomposition during an opioid therapy. An assessment is made as to theseverity of withdrawal symptoms once the opioid is discontinued at thedifferent occasions.

Inhibition of dependence can also be assessed by comparing the magnitudeand/or duration of dependence in different subjects being treated withthe same opioid, some of whom were administered the pharmaceuticalcomposition during a therapy and some whom were not administered thepharmaceutical composition during a therapy. An assessment is made as tothe severity of withdrawal symptoms once the opioid is discontinuedbetween the different subjects.

Typically, dependence is inhibited by at least about 10%, at least about20%, at least about 30%, at least about 40%, at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, or about 100%.

The pharmaceutical composition comprises a) at least one non-steroidalanti-inflammatory drug (“NSAID”), and b) a co-agent.

The NSAID of the present invention includes any NSAID and salts thereof.Examples of suitable NSAIDs include, but are not limited to, aspirin(i.e., acetylsalicylic acid); ibuprofen (i.e., isobutylphenylpropanoicacid); naproxen (i.e., 6-methoxy-α-methyl-2-naphthaleneacetic acid);diclofenac (i.e., 2-[(2,6-dichlorophenyl)-amino]benzene acetic acid);diflunisal (i.e., 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid);etodolac (i.e.,(RS)-2-(1,8-diethyl-4,9-dihydro-3H-pyrano[3,4-b]indol-1yl)acetic acid);indomethacin (i.e.,2-{1-[(4-chlorophenyl)-carbonyl]-5-methoxy-2-methyl-1H-indol-3-yl}aceticacid); ketoprofen (i.e., 3-benzoyl-α-methylbenzeneacetic acid);ketorolac (i.e., 2-amino-2-(hydroxymethyl)-1,3-propanediol); meloxicam(i.e.,4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide);nabumetone (i.e., 4-(6-methoxy-2-naphthyl)-2-butanone); oxaprozin (i.e.,3-(4,5-diphenyl-1,3-oxazol-2-yl)propanoic acid); piroxicam (i.e.,4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-3-carboxamide1,1-dioxide); salsalate (i.e., 2-(2-hydroxybenzoyl)-oxybenzoic acid);sulindac (i.e.,{(1Z)-5-fluoro-2-methyl-1-[4-(methylsulfinyl)-benzylidene]-1H-indene-3-yl}aceticacid); and tolmetin (i.e.,[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid).

Suitable co-agents include desloratadine (i.e.,8-chloro-6,11-dihydro-11-(4-piperdinylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine);fexofenadine (i.e., (±)-4-[1hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-α,α-dimethylbenzeneacetic acid); ketotifen; cetirizine; and salts of such co-agents.

The NSAIDs and co-agents include all pharmaceutically acceptableversions of the NSAIDs and co-agents, including, for example,stereoisomers and/or any mixtures thereof, all pharmaceuticallyacceptable zwitterions and/or any mixtures thereof, all pharmaceuticallyacceptable polymorphic forms and/or any mixtures thereof, and allpharmaceutically acceptable complexes (including solvates) and/or anymixtures thereof.

Salts include all salts of NSAIDs and of co-agents which arepharmaceutically acceptable (i.e., non-toxic at therapeuticallyeffective doses). And, salts include their racemates, enantiomers, orany mixtures thereof.

Particularly suitable salts of the NSAIDs comprise alkali-metal salts(e.g., sodium and/or potassium salts), alkaline earth metal salts (e.g.,magnesium and/or calcium salts), aluminum salts, ammonium salts, saltsof suitable organic bases (e.g., salts of alkylamines and/or-methyl-D-glutamine), salts of amino acids (e.g., salts of arginineand/or lysine). The NSAID salts also include all enantiomeric saltsformed with pharmaceutically acceptable chiral acids and/or bases and/orany mixtures of enantiomers of such salts (e.g., (+) tartrates, (−)tartrates and/or any mixtures thereof including racemic mixtures). Forexample, a typical salt of an NSAID is naproxen sodium.

Examples of suitable salts of the co-agents include ketotifen fumarate,fexofenadine hydrochloride and cetirizine hydrochloride.

The actual preferred amounts of a pharmaceutical composition in aspecified case will vary according to the particular compositionformulated, the mode of application, the particular sites ofapplication, and the subject being treated (e.g., age, gender, size,tolerance to drug, etc.).

Examples of typical daily amounts of NSAIDs to be administered in themethods of the present invention follows. The daily amounts can beadministered in one dose, or in multiple doses, typically, two doses.

Naproxen from about 110 mg to about 1500 mg: Examples of other lowerboundaries of this range include about 150 mg, about 220 mg, about 275mg, about 320 mg and about 420 mg. Examples of other upper boundaries ofthis range include about 580 mg, about 680 mg, about 780 mg, about 880mg and about 950 mg.

Ibuprofen from about 100 mg to about 3200 mg: Examples of other lowerboundaries of this range include about 200 mg, about 400 mg, about 600mg, about 700 mg, about 950 mg and about 1000 mg. Examples of otherupper boundaries of this range include about 1200 mg, about 1500 mg,about 1600 mg, about 2000 mg, about 2500 mg and about 3000 mg.

Aspirin from about 250 mg to about 4000 mg: Examples of other lowerboundaries of this range include about 325 mg, about 450 mg, about 550mg, about 700 mg, about 1000 mg, about 1500 mg, and about 1800 mg.Examples of other upper boundaries of this range include about 2000 mg,about 2500 mg, about 3000 mg, about 3500 mg, and about 3800 mg.

Examples of typical daily amounts of the co-agent to be administered inthe methods of the present invention follows. The daily amounts can beadministered in one dose, or in multiple doses, typically, two doses.

Fexofenadine from about 25 mg to about 200 mg: Examples of other lowerboundaries of this range include about 60 mg, about 70 mg, about 80 mgand about 90 mg. Examples of other upper boundaries of this rangeinclude about 100 mg, about 120 mg, about 150 mg and about 180 mg.Ketotifen from about 0.5 mg to about 3 mg, or about 0.5 mg to about 4mg: Examples of other lower boundaries of this range include about 1 mg,about 1.5 mg and about 1.8 mg. Examples of other upper boundaries ofthis range include about 2 mg, about 2.5 mg and about 2.8 mg, and about3.5 mg. Desloratidine from about 2 mg to about 40 mg: Examples of otherlower boundaries of this range include about 5 mg, about 6 mg and about7 mg. Examples of other upper boundaries of this range include about 8mg, about 9 mg and about 10 mg. Cetirizine from about 2 mg to about 10mg: Examples of other lower boundaries of this range include about 5 mg,about 6 mg and about 7 mg. Examples of other upper boundaries of thisrange include about 8 mg, about 9 mg and about 10 mg.

In one embodiment of the invention, a pharmaceutical compositioncomprises about 800 mg ibuprofen and about 60 mg fexofenadine. Thepharmaceutical composition can be administered every twelve hoursbeginning before the last dose of an opioid is taken, preferably bydelayed release administration.

In one embodiment of the invention, a pharmaceutical compositioncomprises about 1200 mg to about 1600 mg ibuprofen and about 1 mgketotifen, administered to result in a daily dose of about 2400 mg toabout 3200 mg ibuprofen and about 2 mg ketotifen. For example, thepharmaceutical composition can be administered every twelve hoursbeginning before the last dose of an opioid is taken, preferably bycontrolled release administration.

The pharmaceutical composition can be administered by methods known inthe art. For example, the pharmaceutical composition can be administeredsystemically. For the purposes of this specification, “systemicadministration” means administration to a human by a method that causesthe compositions to be absorbed into the bloodstream.

In one embodiment, the pharmaceutical compositions are administeredorally by any method known in the art. For example, the compositions canbe administered in the form of tablets, including, e.g.,orally-dissolvable tablets, chewable tablets; capsules; lozenges; pills(e.g., pastilles, dragees); troches; elixirs; suspensions; syrups;wafers; chewing gum; strips; films (e.g., orally-dissolving thin films);soluble powders; effervescent compositions; and the like.

The NSAID (and/or salt thereof) and the co-agent can be supplied incombination as one unit dose, or can be supplied individually, e.g.,supplied in a package with a unit dose of NSAID and a unit dose of theco-agent.

Additionally, the pharmaceutical compositions can be administeredenterally or parenterally, e.g., intravenously; intramuscularly;subcutaneously, as injectable solutions or suspensions;intraperitoneally; sublingually; or rectally (e.g., by suppositories).Administration can also be intranasally, in the form of, for example, anintranasal spray; or transdermally, in the form of, for example, apatch.

The pharmaceutical composition compounds of the invention can beformulated per se in pharmaceutical preparations, optionally, with asuitable pharmaceutical carrier (vehicle) or excipient, as understood bypractitioners in the art. These preparations can be made according toconventional chemical methods.

In the case of tablets for oral use, carriers commonly used includelactose and corn starch, and lubricating agents such as magnesiumstearate are commonly added. For oral administration in capsule form,useful carriers include lactose and corn starch. Further examples ofcarriers and excipients include milk, sugar, certain types of clay,gelatin, stearic acid or salts thereof, calcium stearate, talc,vegetable fats or oils, gums and glycols.

When aqueous suspensions are used for oral administration, emulsifyingand/or suspending agents are commonly added. In addition, sweeteningand/or flavoring agents may be added to the oral compositions.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the pharmaceutically compositions can be employed,and the pH of the solutions can be suitably adjusted and buffered. Forintravenous use, the total concentration of the solute(s) can becontrolled in order to render the preparation isotonic.

A preferred embodiment of the invention is an orally dissolving tabletcomprising an NSAID and a coagent with or without a taste maskingingredient, diluents, etc. Such tablet can be administered without wateronto the tongue leading to immediate dissolution and is absorbedgastrointestinally or buccally. Orally dissolving tablets can beformulated by a number of techniques including compression andlyophilization, as would be known to a skilled artisan.

Another preferred embodiment of the invention is a lozenge or trochecomprising an NSAID and a coagent with or without a taste maskingingredient, diluents, etc. Such lozenge/troche can be administeredwithout water, and can slowly dissolve in the mouth, or can be swallowedor chewed. Such lozenges/troches can be formulated by compression, aswould be known to a skilled artisan.

The pharmaceutical compositions of the present invention can furthercomprise one or more pharmaceutically acceptable additionalingredient(s) such as alum, stabilizers, buffers, coloring agents,flavoring agents, and the like. In some embodiments, orally administeredpharmaceutical compositions can contain breathe neutralizers, e.g.,peppermint or menthol scents.

The pharmaceutical composition may be administered by controlledrelease. Controlled release administration is a method of drug deliveryto achieve a certain level of the drug over a particular period of time.The level typically is measured by plasma concentration. Methods forcontrolled release of drugs are well known in the art.

The pharmaceutical compositions can be formulated for controlledrelease. For example, in one embodiment, the composition can be acapsule containing beadlets, wherein some of the beadlets dissolveinstantaneously and some of the beadlets dissolve at delayed times dueto different types of beadlet coatings. For example, a controlledrelease composition can be administered twice a day, twelve hours apart.

In one embodiment, the pharmaceutical composition comprises an activeingredient, wherein the active ingredient consists of: a) NSAID, and b)a co-agent selected from the group consisting of: fexofenadine,ketotifen, desloratadine, cetirizine, salts thereof and combinationsthereof.

In one embodiment, the pharmaceutical composition consists of: a) NSAID,and/or salt thereof, b) a co-agent selected from the group consistingof: fexofenadine, ketotifen, desloratadine, cetirizine, salts thereof,and combinations thereof; and c) at least one carrier and/or excipient.

In one embodiment, the pharmaceutical composition consists essentiallyof the active ingredients of: a) NSAID and/or salt thereof, and b) aco-agent selected from the group consisting of: fexofenadine, ketotifen,desloratadine, cetirizine, salts thereof and combinations thereof. Thatis, any other ingredients that may materially affect the basic and novelcharacteristics of the active ingredients of the invention arespecifically excluded from the composition. Any ingredient which canpotentially cause an undesirable effect/side effect, including, forexample, an allergic response, may materially affect the basic and novelcharacteristics of the active ingredients of the invention.

The following are some examples of components which may materiallyaffect the basic and novel characteristics of the active ingredients ofthe pharmaceutical compositions and may be excluded from certainembodiments of the present invention: cyclooxygenase-2-selectiveinhibitors (i.e., COX-2-selective inhibitors) or prodrugs thereof;sedating antihistamines (e.g., phenyltoloxamine (e.g., phenyltoloxaminecitrate), doxylamine (e.g., doxylamine succinate)); antiemeticantihistamines (e.g., dimenhydrinate (Dramamine®), clizines (e.g.,cyclizine, meclizine), diphenhydramine (Benadryl®), promethazine(Pentazine®, Phenergan®, Promacot®), and hydroxyzine (Vistaril®));decongestants; flunixin meglumine (i.e., banamine); 5-HT3 receptorantagonists; cough suppressants (e.g., guaifenesin, dextromethorphan);H₂ antihistamines and corticosteroids.

The aforementioned ingredients may materially change the characteristicsof the present pharmaceutical composition due to unwanted effects and/orpotential allergic responses.

Examples of unwanted potential effects of COX-2-selective inhibitors, orprodrugs thereof, include an increased risk in the incidence ofmyocardial infarctions. COX-2-selective inhibitors are compounds whichselectively inhibit cyclooxygenase-2 over cyclooxygenase-1, and alsoinclude pharmaceutically acceptable salts of such compounds, andprodrugs of such compounds. A COX-2 selective inhibitor is any inhibitorfor which the ratio of COX-1 IC₅₀ to COX-2 IC₅₀ is greater than 1.Examples of unwanted potential effects of sedating antihistamines,decongestants, and diphenhydramine include sleepiness, fatigue,dizziness, headache, dry mouth, difficulty urinating or an enlargedprostate and allergic reactions. Examples of unwanted potential effectsof flunixin meglumine include ataxia, incoordination, hyperventilation,hysteria and muscle weakness. Examples of unwanted potential effects of5-HT3 receptor antagonists include constipation, diarrhea, headache,dizziness and arrhythmias. Examples of unwanted potential effects ofguaifenesin include diarrhea, dizziness, headache, hives, nausea orvomiting, skin rash and stomach pain. Examples of unwanted potentialeffects of dextromethorphan include confusion, constipation, dizziness,drowsiness, headache, nausea or vomiting and stomach pain. Examples ofunwanted potential effects of H₂ antihistamines include abdominal pain,bleeding or crusting sores on lip, dizziness, fainting, fever andchills. Examples of unwanted potential effects of corticosteroidsinclude fluid retention, edema, weight gain, high blood pressure,headache and muscle weakness.

In one embodiment, the pharmaceutical composition is combined with anopioid during opioid therapy, i.e., instead of being given the opioidseparately. That is, an NSAID, a co-agent and an opioid are formulatedinto a single pharmaceutical preparation, optionally, with a suitablepharmaceutical carrier (vehicle) or excipient, as understood bypractitioners in the art. These preparations can be made according toconventional chemical methods, as described above.

In one embodiment, the pharmaceutical composition is administered duringmethadone detoxification therapy. Such therapy can either be donerelatively rapidly in less than a month or gradually over as long as sixmonths.

Opioid therapy can last for about two to eight weeks, or indefinitely.During such period, the pharmaceutical composition can be administeredon a substantially daily basis. Daily NSAID use has been associated withadverse gastrointestinal effects (e.g., upset stomach, ulcers). However,when the NSAIDs of the present invention are taken in combination withthe co-agents, adverse gastrointestinal effects are surprisingly slightor absent. Thus, it has unexpectedly been found that the components ofthe compositions of the present invention have a synergistic effect wheninhibiting the adverse symptoms associated with the withdrawal fromopioids.

Thus, while there have been described what are presently believed to bethe preferred embodiments of the present invention, other and furtherembodiments, modifications, and improvements will be known to thoseskilled in the art, and it is intended to include all such furtherembodiments, modifications, and improvements as come within the truescope of the claims as set forth below.

The invention claimed is:
 1. A method of inhibiting dependence to anopioid by a human subject in need thereof, comprising: administering aneffective amount of a pharmaceutical composition to the subject duringopioid therapy, wherein the pharmaceutical composition comprises: a) anon-steroidal anti-inflammatory drug (NSAID); and b) a co-agent selectedfrom the group consisting of: fexofenadine, ketotifen, desloratadine,cetirizine, salts thereof and combinations thereof; wherein dependenceto an opioid is inhibited in the human subject, wherein the opioid isselected from the group consisting of: opium, heroin, morphine, codeine,thebaine, hydrocodone, oxycodone, fentanyl, methadone, pethidine andhydromorphone.
 2. The method of claim 1 wherein the NSAID is selectedfrom the group consisting of: aspirin, ibuprofen, naproxen, diclofenac,diflunisal, etodolac, indomethacin, ketoprofen, ketorolac, meloxicam,nabumetone, oxaprozin, piroxicam, salsalate, sulindac, and tolmetin. 3.The method of claim 1 wherein the NSAID is ibuprofen and the co-agent isfexofenadine.
 4. The method of claim 1 wherein the amount of ibuprofenis about 150 mg to about 900 mg, and the amount of fexofenadine is about60 mg to about 180 mg.
 5. The method of claim 1 wherein the ibuprofenand the fexofenadine is combined in one unit dose.
 6. The method ofclaim 1 wherein the ibuprofen and the fexofenadine is in the form of atablet, lozenge or chewing gum.
 7. The method of claim 1 wherein theNSAID is ibuprofen and the co-agent is ketotifen.
 8. The method of claim1 wherein the amount of ibuprofen is about 1200 mg to about 1600 mg, andthe amount of ketotifen is about 0.5 mg to about 3 mg.
 9. The method ofclaim 2 wherein the daily dose of ibuprofen is about 2400 mg to about3200 mg, and the daily dose of ketotifen is about 2 mg.
 10. The methodof claim 9 wherein the ibuprofen and the ketotifen is combined in oneunit dose.
 11. The method of claim 10 wherein the ibuprofen and theketotifen is in the form of a tablet, lozenge or chewing gum.
 12. Amethod of inhibiting dependence to an opioid by a human subject in needthereof, comprising: administering to the subject an effective amount ofa pharmaceutical composition during an opioid therapy, wherein thepharmaceutical composition consists essentially of: a) about 1200 mg toabout 1600 mg of ibuprofen, and b) about 0.5 mg to about 3 mg ketotifen,wherein dependence to an opioid is inhibited in the human subject,wherein the opioid is selected from the group consisting, of: opium,heroin, morphine, codeine, thebaine, hydrocodone, oxycodone, fentanyl,methadone, pethidine and hydromorphone.
 13. The method of claim 12wherein a daily dose of ibuprofen is about 2400 mg to about 3200 mg, andthe a daily dose of ketotifen is about 2 mg.
 14. The method of claim 12wherein the ibuprofen and the ketotifen are combined in one unit dose.15. The method of claim 12 wherein the ibuprofen and the ketotifen arein the form of a tablet, lozenge or chewing gum.